FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"NOVEL PROCESSES FOR PREPARATION OF XANTHINE OXIDASE
INHIBITOR"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies Act, 1956
(c) ADDRESS: 289, Betlasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

Technical Field of the Invention:
The present invention relates to novel processes for the preparation of 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-5-thaizole carboxylic acid or a pharmaceutically acceptable salt thereof.
Background of the Invention:
Febuxostat is an inhibitor of xanthine oxidase and it is useful in the treatment of hyperuricemia and gout. The chemical name for febuxostat is 2-[3-cyano-4-(2-methylpropoxy)phenyl]-4-rnethyl-5-thaizole carboxylic acid which is represented by following formula (I).

EP0513379 and its equivalent US5614520 disclose 2-arylthiazole derivatives and pharmaceutically acceptable salts thereof.
JP6-329647, JP6-345724 and JP10-45733 disclose various methods for the preparation of febuxostat.
WO2005012273 discloses a method for the preparation of intermediates used in the preparation of febuxostat.
Although febuxostat and its pharmaceutically acceptable salts have been made by various processes as disclosed in the prior art, there still exists a need to develop a process which is more economical, efficient and industrially feasible.


comprising reacting an intermediate A;

with intermediate compound of formula B;

to the intermediate ester of febuxostat


and hydrolyzing the intermediate ester of febuxostat to febuxostat of formula I. wherein R' is an activating group selected from boronic acid or lithium; R is selected from optionally substituted C1-4 alkyl or optionally substituted aryl; L is a leaving group selected from diazo, halogen, -OS02R" or-OCOR" or -0-Si(R")3; and R" is selected from optionally substituted C1-4 alkyl or optionally substituted aryl.
The prior art processes disclosed in the citations listed above involve the use of toxic reagents such as thioacetamide, potassium cyanide and hydrogen sulphide. The inventors have devised a highly-advantageous in that it avoids the use of toxic reagents. The process of the present invention instead involves the use of simple reagents and solvents. The inventors have surprisingly found that the use of the simple reagents and solvents reduces the number of steps involved in the preparation of febuxostat. Thus, the process of the present invention is highly-suitable for industrial scale-up.
The condensation and hydrolysis steps may be carried out without isolating the intermediate ester of febuxostat.
In the context of the present invention, the term "without isolation" means that the product referred is not isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid. Thus, "without isolation" may mean that the product remains in solution and is then used directly in the next synthetic step, or it may mean that solvent is substantially removed from a solution of the product such that the product is present as a residue, but not as a solid.
The halogen may be selected from chloro or bromo, preferably bromo.

The C1-4 alkyl may be methyl, ethyl, i-propyl, n-propyl, n-butyl or i-butyl, typically methyl or ethyl. Aryl may be phenyl. Thus, R may be methyl, ethyl, i-propyl, n-propyl, n-butyl or i-butyl, typically methyl, ethyl or phenyl, or substituted methyl, ethyl, i-propyl, n-propyl, n-butyl or i-butyl, typically methyl, ethyl or phenyl. R" may be methyl, ethyl, i-propyl, n-propyl, n-butyl or i-butyl, typically methyl, ethyl or phenyl, or substituted methyl, ethyl, i-propyl, n-propyl, n-butyl or i-butyl, typically methyl, ethyl or phenyl.
The coupling reaction is carried out in the presence of a metallic compound catalyst and base in a suitable solvent.
The metallic compound may be selected from palladium, nickel, rhodium, ruthenium, a metallic salt and a metallic complex. Preferably the metallic compound is a palladium (0) ligand complex selected from bis-acetylacetonato palladium (II), palladium tri tert-butyl phosphine, palladium trifluoroacetate, bis-(dibenzylideneacetone) palladium (0), Pd salt/Pd(N,N-dimethyl β-alaninate)2 tris(dibenzylidene acetone) dipalladium [Pd2(dba)3], Tetrakis(triphenylphosphine)palladium(0) Pd[P(C6H5)3]4, dichloro[I ,l-bis(diphenyl phosphino) ferrocene]palladium (II) [PdCl2(dppf)], 1,4- bis(diphenylphosphino) butane palladium (II) chloride [PdCb(dppb)], dichlorobis(tricyclohexylphosphine) palladium (II) [PdCl2(PCy3]2], dichloro[l,1-bis(di-tert-butylphosphino)ferrocene]palladium (II) [PdCl2(dtbp)], palladium black, palladium chloride, palladium acetate, palladium catalysts over polymeric supports and other palladium homogeneous catalysts. The preferred catalyst is tetrakis (triphenyl phosphene) palladium(0).
The reaction may be palladium-catalyzed cross coupling reaction between organoboronic acid and halide compound.
The catalyst used may advantageously be commercially available and may be used as such in the reaction or may be prepared in situ by reacting a metal salt with a ligand, for example reacting palladium chloride or palladium acetate with triphenyl phosphene to obtain tetrakis (triphenyl phosphene) palladium (0).

The base used for the reaction may be an inorganic base such as sodium methoxide, sodium ethoxide, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate or lithium carbonate, preferably sodium carbonate, more preferably an aqueous base.
The solvent used for coupling reaction the solvent may be selected from the group consisting of aromatic hydrocarbons, aprotic polar solvents, protic polar solvents, aliphatic ethers, mixtures of water and one or more organic solvents. Preferably the solvent is toluene.
The reaction may be carried out at a temperature ranging from 50-100°C, preferably 70-80°C.
The ester of febuxostat is further hydrolyzed in the presence of a base or an acid in a suitable solvent to obtain febuxostat.
If a base is used for the hydrolyzation, it may be selected from the group consisting of sodium hydroxide or potassium hydroxide. If an acid is used for the hydrolyzation, it may be selected from the group consisting of hydrochloric acid or sulfuric acid.
The solvent used for hydrolysis is preferably selected from tetrahydrofuran (THF), water, methanol, ethanol, propanol or mixtures thereof.
The hydrolysis step is preferably carried out at a temperature ranging from about 30°C to about reflux temperature.
In an embodiment, R' is boronic acid and the intermediate A is designated as (Al)


The compound of formula (Al) may be obtained by a process which comprises steps i), (ii) and (iii), as described below.
Step i): reacting 5-bromo-2-hydroxybenzaidehyde

with an isobutyl halide selected from the group consisting of isobutyl bromide, isobutyl chloride and isobutyl iodide, preferably isobutyl bromide, in the presence of a base in a solvent to obtain compound III;

The solvent used for the reaction may be selected from polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; or ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; optionally substituted hydrocarbon such as methylene dichloride, toluene, xylene; or water.
A suitable base used for the reaction may be an inorganic or organic base. The inorganic base may be selected from the group consisting of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or barium carbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide or barium hydroxide. Organic bases may be aliphatic or aromatic and may be selected from, but not limited to triethyl amine, di-

isopropyl amine, pyridine, picoline, diethyl amine, piperidine, N,N-diisopropylethylamine.
The temperature at which reaction proceeds is typically in the range of 70-100°C.
Step ii): treating compound III with hydroxylamine or a salt thereof in the presence of a dehydrating agent and a base to obtain compound IV.

The dehydrating agent used may be selected from formic acid, acetic acid, acetic anhydride, propane phosphonic acid anhydride, polyphosphonic acid, a trihaloacetic acid, sulfuric acid, trimethylorthoformate or phosphorous pentoxide. The trihalo acetic acid may be trichloroacetic acid, tribromoacetic acid or trifluoroacetic acid.
The base used may be selected from sodium formate, sodium acetate, ammonium formate or ammonium acetate.
The temperature at which reaction is carried out typically ranges from 90-110°C.
Step iii): reacting compound IV with an organo lithium compound in a solvent to yield compound V;

followed by reaction with trialkyl borate and subsequent hydrolysis with an acid to give Intermediate AI.

In an embodiment, the reaction is carried out without isolation of intermediate compound
V.
The organo lithium compound used may be selected from the group consisting of n-butyl lithium, isobutyl lithium, phenyl lithium, lithium diisopropyl amine (LDA), n-hexyl lithium and sec-butyl lithium.
The trialkyl borate used may be selected from trimethyl borate, triethyl borate, triisopropyl borate, triisobutyl borate and tri-n-butyl borate, preferably triisopropyl borate.
The solvent used may be selected from ethers which includes aliphatic straight chain ethers such as dimethyl ether, diethyl ether, ethyl methyl ether; cyclic ether such as tetrahydrofuan, 1,4-dioxane; aromatic ethers such as diphenyl ether.
The temperature at which reaction is carried out typically ranges from -60 to -400C.
The acid used for hydrolysis may be a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or organic acid such as acetic acid, formic acid, propionic acid. Preferably the acid used is sulfuric acid.
In an embodiment R' is a Grignard reagent (i.e. MgX, wherein X is a halo) and the process for preparing this embodiment of intermediate A comprises; reacting I-isobutoxy-2-cyano-4-halo benzene (compound IV) with magnesium metal in the presence of a solvent to obtain the corresponding aryl magnesium halide (Grignard reagent), followed by reaction with trialkyl borate and subsequent hydrolysis with an acid to give Intermediate Al.
In an embodiment, L is bromo and the intermediate B is designated as (B1)


wherein R is as defined above.
Thus, according to another aspect of the present invention, there is provided a process for preparation of intermediate Bl which comprises steps (i) and (ii), as described below
Step (i): reacting thiourea with a 2-chloroacetoacetic acid alkyl ester in the presence of a suitable solvent to obtain compound 1.

wherein R is as defined above,
The solvent may be selected from the group consisting of a C1-4 alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol; or an inert solvent such as acetonitrile, toluene or xylene.
The temperature at which the reaction is carried out is suitably below 70°C.

Step ii): diazotizing and then brominating compound 1 using a diazotizing agent/deaminating agent and brominating agent, respectively in the presence of a solvent to obtain compound Bl.
The diazotizing agent/deaminating agent may be selected from the group consisting of alkyl nitrite such as ethyl nitrite, n-propyl nitrite, isopropyl nitrite, n-butyl nitrite, isobutyl nitrite, t-butyl nitrite, isopentyl nitrite or isoamyl nitrite; or an alkali metal nitrite such as sodium nitrite or potassium nitrite.
The brominating agent used may be selected from bromine, aqueous bromine, bromine in acetic acid, metal bromide such as copper bromide, zinc bromide, nickel bromide, sodium bromide, potassium bromide, bromoform.
The solvent may be selected from non aqueous polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioaxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; inert solvent such as acetonitrile, toluene, xylene.
In an embodiment, compound 1 is treated with cuprous halide, preferably cuprous bromide in the presence of t-butyl nitrile to yield compound B1.
In yet another aspect of the present invention, aqueous diazotization of compound 1, may be carried out using sodium nitrite in water to yield compound II

wherein R is as defined above.
The compound II obtained after aqueous diazotization may further be treated with either trisubstituted silyl halide or anhydride compound or carboxylic acid chloride or substituted sulfonyl chloride to give the corresponding novel compound B2


or novel compound B3 or novel compound B4

by using processes known in the art.
The reaction may be carried out at a temperature in the range of 40-70°C.
According to another aspect of the present invention, there is provided a process for preparing febuxostat comprising subjecting compound B2, B3 or B4 to condensation with compound A to form an intermediate ester of febuxostat followed by hydrolysis to yield febuxostat of formula I.
In yet an alternative embodiment of the present invention, the process for the preparation of febuxostat comprises converting compound IV to compound V by treatment with an organolithium compound


wherein the reaction is preferably carried out at a temperature below 0°C, more preferably in the range of -20 to -40°C; and condensing with compound B, to obtain the ester of febuxostat, followed by hydrolysis.
The condensation and hydrolyzation steps may be carried out without isolation of the compound V.
In JP1998045733, example 1, the ester of 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid is formylated in polyphosphoric acid, to yield 63% of compound VI, 2-(3-formyl-4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid, contaminated with 2% residual raw material. However, on repeating this procedure in laboratory, it was observed that, addition of water and acetic acid causes the material to become hard and hence was difficult to isolate from the reaction vessel. Further, the isolated material was inferior in quality and hard in nature and hence was difficult to purify. This, further, resulted in the low yield of 52% and low purity of 85% of cyano intermediate. Further, the intermediate was contaminated with unidentified impurities which were difficult to separate during the isolation of febuxostat, and resulted in the febuxostat having low purity and low yield.
Further, preparation of polyphosphoric acid involves mixing of phosphorous pentoxide and phosphoric acid. Handling of phosphorous pentoxide and phosphoric acid is difficult on industrial scale. The said patent also describes, the high content of polyphosphoric acid i.e. >115%, is indicative of high viscosity of polyphosphoric acid and hence requires auxiliary solvent such as acetic acid, sulfuric acid, tetrahydrofuran, methane sulfonic acid (4-5%), p-tolyl sulfonic acid.

In JP6329647, formylation reaction is carried out using trifluoroacetic acid which results in the 40% yield of febuxostat.
The processes described in these two Japanese patents require extraction using organic solvents such as ethyl acetate, methylene dichloride. Use of such solvents makes the process lengthy, costly and also contributes to the environmental pollution.
It has surprisingly been found that the use of a combination of polyphosphoric acid (1 vol) with methane sulfonic acid (10 vol) proved to be advantages over prior art solvents as it increased the yield of formylated intermediate from 63 % to 80% having purity of 90%.
Alternatively the formylation of 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid was found to be more effective than the corresponding ester with respect to the yield and purity.
According to another aspect of the present invention, there is provided a process for preparing a compound of formula IX

wherein Rl and R2 are the same or different and are selected from optionally substituted alkyl, which process comprises:
a) formylating a compound of formula VI with a formylating agent in the presence of an organic solvent to form compound VII,

wherein Rl is H or optionally substituted alkyl;
b) alkylating compound VII using an alkylating agent in the presence of an organic solvent to obtain compound VIII,

wherein Rl and R2 are the same or different and are selected from optionally substituted alkyl; and
c) reacting compound VIII with hydroxylamine or a salt thereof in the presence of a dehydrating agent to obtain the compound of formula IX

wherein Rl and R2 are same or different and are selected from optionally substituted alkyl.
When Rl on compound VI is hydrogen, the hydrogen will be alkylated in step (b), and Rl and R2 will be the same and will correspond to the alkyl of the alkylating agent.

When Rl on compound VI is optionally substituted alkyl, the Rl group will not be alkylated in step (b), and Rl and R2 may be the same or different. R2 will correspond to the alkyl of the alkylating agent.
Alternatively, the compound of formula VI11 may be prepared by a process comprising the steps of: (a) alkylating compound VI, using an alkylating agent in the presence of an organic solvent to obtain compound X;

Compound X
wherein Rl and R2 are same or different and are selected from optionally substituted alkyl; and (b) formylating the compound of formula X with a formylating agent in the presence of an organic solvent to form compound VIII.
When Rl on compound VI is hydrogen, the hydrogen will be alkylated in step (b), and Rl and R2 will be the same and will correspond to the alkyl of the alkylating agent.
When Rl on compound VI is optionally substituted alkyl, the Rl group will not be alkylated in step (b), and Rl and R2 may be the same or different. R2 will correspond to the alkyl of the alkylating agent.
The formylation reaction is preferably carried out using hexamine in the presence of methane sulfonic acid at a temperature ranging from 50-100°C. Preferably, the reaction is carried out at 80-85°C.
The alkyalting agent may be selected from an optionally substituted alkyl halide. The alkyalation is carried out in the presence of a suitable polar solvent such as DMSO, DMF, THF or acetone; typically at a temperature ranging from about ambient to the reflux temperature of the solvent used. Further, the reaction can also be carried out optionally in the presence of, potassium iodide to accelerate the reaction.

The dehydrating agent used in the step c) may be selected from formic acid-sodium formate, acetic anhydride or P0C13. Further, the reaction may be carried out optionally in the presence of either an organic or inorganic base.
When R2 is an isobutyl group, the compound of formula IX is the ester of febuxostat and the process of the present invention further comprises: converting the ester of febuxostat of formula IX to febuxostat.
The conversion may comprise hydrolyzing the ester of febuxostat of formula IX using a hydrolyzing agent such as an organic or inorganic base in the presence of a solvent to give febuxostat. Preferably, the reaction is carried out in water, an alcoholic solvent such as methanol, ethanol, isopropanol, n-butanol or tert-butanol. The base may be selected from an alkaline metal hydroxide such as sodium hydroxide or potassium hydroxide; an alkaline metal carbonate such as sodium carbonate or potassium carbonate; alkaline metal bicarbonate such as sodium bicarbonate or potassium bicarbonate. More prefeably alkaline metal hydroxide is sodium hydroxide. Reaction is carried out at a temperature of about 25°C to reflux temperature of the solvent used. A preferred temperature range is at about 75-85°C.
This improved process also results in the simplified work up procedure by avoiding extraction, using organic solvents and purification of the intermediates by using water as a solvent for isolation and purification. All these advantages form another aspect of the present invention.
According to yet another aspect of the present invention there is provided novel compounds B2, B3 and B4. The compounds may be prepared according to the processes described above.
There is also provided by the present invention febuxostat or its pharmaceutically acceptable salt thereof prepared by a process as described above.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising febuxostat or its pharmaceutically acceptable salt thereof, prepared by a process as described above, together with one or more pharmaceutically acceptable excipients. Such excipients are well known to those skilled in the art.
According to another aspect of the present invention, there is provided the use of febuxostat or its pharmaceutically acceptable salt thereof, prepared by a process as described above in medicine.
According to another aspect of the present invention, there is febuxostat or its pharmaceutically acceptable salt thereof, prepared by a process as described above for use in the treatment of hyperuricemia and/or gout.
According to another aspect of the present invention, there is provided the use of febuxostat or its pharmaceutically acceptable salt thereof, prepared by a process as described above, in the manufacture of a medicament for treating hyperuricemia and/or gout.
According to another aspect of the present invention, there is provided the use of febuxostat or its pharmaceutically acceptable salt thereof, prepared by a process as described above in the treatment of hyperuricemia and gout.
According to another aspect of the present invention, there is provided a method of treating hyperuricemia and gout in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of febuxostat or its pharmaceutically acceptable salt thereof, prepared by a process as described above.
Detailed Description of the Invention:
The present invention provides a process for the preparation of febuxostat which process is economical, fast and which results in a high purity febuxostat product.

In an embodiment, febuxostat or a pharmaceutically acceptable salt thereof, is prepared by a process which comprises aryl-heteroaryl coupling of intermediate A with intermediate B.
Accordingly, an embodiment of the process for the preparation of febuxostat is as shown in Scheme A.

wherein R' is an activating group selected from boronic acid or lithium; R is selected from optionally substituted C1-4 alkyl or optionally substituted aryl; L is a leaving group which can be diazo, halogen, -OS02R" or -OCOR" or -0-Si(R")3 and R" is selected from optionally substituted C1-4 alkyl or optionally substituted aryl.
Preferably, the coupling reaction is carried out in the presence of a catalyst comprising a metallic compound catalyst, and in the presence of a base and a suitable solvent.
Typically, intermediate A is reacted with intermediate B to yield febuxostat without isolating the intermediate ester of febuxostat.

The metallic compound may be selected from palladiuri1' nickel, rhodium, ruthenium, a
metallic salt and a metallic complex. Preferably the metallic compound is a palladium (0)
ligand complex selected from;
bis-acety lacetonato pal lad iurn (11),
palladium tri-tert-butyl phosphine,
palladium trifluoroacetate,
bis-(dibenzylideneacetone)palladium(0),
Pd salt/Pd(N,N-dimethyl β-alaninate)2,
tris(dibenzylideneacetone)dipalladium [Pd2(dba)3],
Tetrakis(triphenylphosphine)palladium(0)Pd[P(C6H5)3]4,
dichloro[l,l-bis(diphenylphosphino)ferrocene]palladium(11) [pdCl2(dppf)],
l,4-bis(diphenylphosphino)butanepalladium(II)chloride [PdCl2(dppb)],
dichlorobis(tricyclohexylphosphine)palladium(II)[PdCl2(pcy3)2]!
dichloro[1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II)[PdCl2(dtbp)],
palladium black,
palladium chloride,
palladium acetate,
palladium catalysts over polymeric supports and
other palladium homogeneous catalysts.
The catalyst used may be commercially-available and used as such in the reaction or may be prepared in situ by reacting a metal salt with a ligand. For example, the catalyst may be prepared in situ by reacting palladium chloride or palladium acetate with triphenyl phosphene to obtain tetrakis(triphenyl phosphene)palladium (0)
The base may be an inorganic base such as sodium methoxide sodium ethoxide, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate or lithium carbonate, preferably sodium carbonate, and more preferably aqueous sodium carbonate.
The solvent may be. selected from the group consisting of water, an aromatic hydrocarbon, a aprotic polar solvent, a protic polar solvent an aliphatic ether, or a mixture of water and one or more organic solvents.

Preferably, the coupling reaction is carried out in the presence of toluene, suitably at a temperature ranging from 50-100°C, preferably 70-80°C.
The process of the present invention may further comprise hydrolyzing the ester of febuxostat with an acid or base to obtain febuxostat of formula (I).
The base for hydrolysis may be sodium hydroxide or potassium hydroxide. The acid for hydrolysis may be hydrochloric acid or sulfuric acid.
The hydrolysis reaction may be carried out in the presence of a solvent selected from the group consisting of THF, water, methanol, ethanol, propanol or mixtures thereof, suitably at a temperature ranging from about 30°C to about the reflux temperature of the solvent used.
The condensation and hydrolysis steps may be carried out without isolating the intermediate ester of febuxostat.
More particularly, the compound of formula (Al) wherein R' is boronic acid may be condensed with the compound of formula (Bl) wherein L is bromo and R is an alkyl ester, to give the corresponding ester of febuxostat which on hydrolysis yields febuxostat of formula (I) as shown in Scheme B. Advantageously, the febuxostat is prepared in a substantially pure form. The R group may be methyl or ethyl.
Scheme 8


The coupling reaction may be a palladium-catalysed cross coupling reaction between the organoboronic acid intermediate Al and intermediate Bl.
The preferred catalyst is tetrakis(triphenylphosphene)palladium which may be prepared in situ by reacting palladium chloride or palladium acetate with triphenylphosphene.
The preferred base is sodium carbonate which may be added as such or as an aqueous solution.
In an embodiment, intermediate Al is prepared as shown in Scheme C.
Scheme C


Alternative activating groups at the 4 position on intermediate A may be prepared. For example, the activating group may be a Grignard reagent. This reagent may be prepared by treating a l-isobutoxy-2-cyano-4-haiobenzene with magnesium metal in the presence of a suitable solvent to obtain the corresponding aryl magnesium halide (Grignard reagent) by the processes known in the art. Suitably, the halo is chloro or bromo. This is followed by reaction with trialkyl borate and subsequent hydrolysis with an acid to give Intermediate A1
The intermediate compound of formula (Bl) useful in the synthesis of febuxostat may be prepared as shown in Scheme D: thiourea is reacted with 2-chloroacetoacetic acid alkyl ester in the presence of a suitable solvent to obtain compound 1, followed by diazotization and then bromination using a suitable diazotizing agent/deaminating agent and brominating agent respectively in the presence of a suitable solvent to obtain Intermediate Bl.
Alternatively, compound 1 may be diazotized using sodium nitrite in water to obtain compound II. The compound II obtained after aqueous diazotization can further be treated with either trisubstituted silyl halide or anhydride compound or carboxylic acid chloride or substituted sulfonyl chloride to give the corresponding novel intermediates B2, B3 or B4 as shown in Scheme D.


In accordance with still another embodiment of the present invention, a modified process for preparing a compound of formula IX is as shown in Scheme E, wherein the process comprises the steps of:
a) formylating a compound of formula VI with a formylating agent in the presence of a suitable organic solvent to form compound VII;
b) alkylating compound VII using a suitable alkylating agent in the presence of a suitable organic solvent to obtain compound VIII; and
c) converting compound VIII to an alkyl ester of febuxostat of formula IX with hydroxyl amine or a salt thereof in the presence of a dehydrating agent.

Alternatively, the compound of formula VIII may be prepared by a process comprising the steps of:
a) alkylating compound VI using a suitable alkylating agent in the presence of a suitable organic solvent to obtain compound X; and
b) formylating the compound of formula X with a formylating agent in the presence of a suitable organic solvent to form compound VIII.


When R2 is an isobutyl group, the compound of formula IX is the ester of febuxostat and the process of the present invention further comprises: converting the ester of febuxostat of formula IX to febuxostat.
The conversion may comprise hydrolyzing the ester of febuxostat of formula IX using a suitable hydrolyzing agent such as an organic or inorganic base in the presence of a suitable solvent to give febuxostat.
Preferably, the conversion is carried out in the presence of a solvent and a base. Preferably, the solvent is an alcoholic solvent, for example selected from methanol, ethanol, isopropanol, n-butanol or tert-butanol, and the base is selected from: an alkaline metal hydroxide such as sodium hydroxide or potassium hydroxide; an alkaline metal carbonate such as sodium carbonate or potassium carbonate; and an alkaline metal bicarbonate such as sodium bicarbonate or potassium bicarbonate. More preferably, an alkaline metal hydroxide is used, most preferably sodium hydroxide.
Preferably, the reaction is carried out at a temperature ranging from about 25°C to the reflux temperature of the solvent used. A preferred temperature range is from about 75-85°C.
While emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.
The details of the invention given in the examples which are provided below are for illustration only and therefore these examples should not be construed to limit the scope of the invention.

Examples:-
Preparation of ethyl 2-amino-4-methylthiazole-S-carboxylate

Thiourea (30 gm/0.3947 moles) was stirred in 150 ml ethanol at room temperature. To the reaction mass ethyl-2-chloroacetoacetate (64 gms/0.389 moles) was added drop wise under constant stirring at room temperature. The reaction mass was heated to 70°C and stirred for. 10-15 minutes at same temperature. The reaction contents was brought to 25-30°C, the solid obtained was isolated by filtration, washed with 100 ml ethanol, and dried under vacuum at 45-50°C for 10 hours to yield 68.0 gms of the titled compound. Efficiency: 93%
Preparation of ethyl 2-bromo-4-methythiazole-5-'carboxylate (compound B: L=bromo; R=ethyl)

To a solution of CuBr2 (75 gms/0.335 moles) in 750 ml acetonitriie was added t-butyi nitrite (28.6 gms/0.277 moles). The resultant mixture was heated to 60°C and ethyl 2-amino-4-methylthiazole-5-carboxylate (35.0 gms/0.188moles) was further added in lots. The reaction mass was stirred for 1 hour at 60°C. After completion of reaction, the reaction mass was cooled to 25°C and about 150 ml water was added. The reaction mass was neutralized using 2N NaOH and extracted in ethyl acetate (300 ml). The organic layer was washed with water until a neutral pH. The separated organic layer was treated with charcoal. After drying the organic layer over anhydrous sodium sulphate, a clear

filtrate was distilled off and ] 7.1 gms of the titled compound was obtained after drying at 40-45°C as an off-white colored solid. Efficiency: 36%
Preparation of 5-bromo-2-isobutoxybenzaldehyde

To a solution of 5-bromosalicylaldeyhde (50 gms/0.2487 moles) in 350 ml of N,N-dimethylformamide was added K2C03 (102 gms/0.7391 moles), followed by addition of iso-butyl bromide (102gms/0.746moles). The resultant mixture was heated to 75-80°C for 2 hours. After completion of reaction, the reaction mass was cooled to 25°C and about 2000 ml water was added. The reaction mixture was extracted in ethyl acetate (500 ml). The organic layer was washed with water until a neutral pH. After drying the organic layer over anhydrous sodium sulphate, clear filtrate was distilled off and 53.0 gms of the titled compound was obtained. Efficiency: 82.9%
Preparation of 5-bromo-2-isobutoxy benzonitrile (compound A: R=bromo)

To a solution of 5-bromo-2-isobutoxy benzaldehyde (50.0 gms/0.1953 moles) in 70 ml of formic acid, was added hydroxylamine hydrochloride (3.5 gms/0.0504 moles), followed by sodium formate (4.25 gms/0.0625 moles) .The resultant mixture was heated to 99-100°Cfor 7 hours. After completion of reaction, the reaction mass was cooled to 25°C and about 2000 ml water was added. The reaction mixture was extracted in ethyl acetate (500 ml). The organic layer was washed with water, dried over anhydrous sodium sulphate and clear filtrate was distilled off to yield 48 gms of the titled compound. Efficiency: 97.9%

Preparation of 3-cyano-4-isobutoxvphenyl boronic acid (compound A: R= -B(OH)2)

A solution of 5-bromo-2-isobutoxy benzonitrile (5.0 gms/0.01968 moles) in 50 ml of THF was cooled to -45°C under nitrogen atmosphere. To the resulting mixture, triisopropyl borate (4.6 gms/0.02446 moles) was added, followed by addition of solution of n-BuLi (20 ml in 15% n-hexane). The resultant mixture was stirred at -40 to -45°C for 3 hours. The temperature of the reaction mass was raised to -20°C and 20 ml of 6N HCI was added. The temperature of the reaction mass was further raised to 25°C and the mass extracted in ethyl acetate (50ml). The organic layer was washed with water, dried over anhydrous sodium sulphate, and the clear filtrate was distilled off to yield 2.2 gms of the titled compound as solid. Efficiency: 51%
Preparation of ethvl-2-(3-cvano-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylate (ethyl ester of febuxostat)

3-cyano-4-isobutoxyphenyl boronic acid (2.0 gms/0.009132 moles), ethyl-2-bromo-4-methylthiazole-5-carboxylate (2.28 gms/0.009132 moles) and 20 ml of 2M aqueous sodium carbonate solution were charged in 30 ml toluene, followed by tetrakis (triphenyl phosphine) palladium (0.6 gms/5 mole%). The resultant mixture was stirred at 70- 75°C for 1 hour. After completion of reaction, the reaction mass was cooled to 25°C and extracted in ethyl acetate (30ml). The organic layer was washed with brine. After drying the organic layer over anhydrous sodium sulphate, clear filtrate was distilled off and the

residue was stirred in diisopropyl ether (30 ml). The resulting solid was isolated by filtration to yield 2.0 gms of the titled compound. Efficiency: 63%
Preparation of Febuxostat

To a solution of ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (2.0 gms/0.006035 moles) in 15 ml of THF was added 4.3ml of 2N NaOH slowly under nitrogen atmosphere at 25-30°C, The resultant mixture was stirred at reflux for 5 hour. The reaction mass was cooled to 25°C and filtered through celite. To the reaction mass concentrated HCI was added followed by 50ml of distilled water. The reaction mass was further stirred for 30 minutes. The resulting solid was isolated by filtration, washed with water until a neutral pH and dried under vacuum to yield 1.3 gms of the titled compound. Efficiency: 72%
Preparation of febuxostat without isolation of intermediate ethyl-2-(3-cyano-4-isobutoxyphenyl)-4-methyl thiazole-5-carboxylate
3-cyano-4-isobutoxyphenyl boronic acid (5.0 gms/0.02283 moles), ethyl-2-bromo-4-methylthiazole-5-carboxylate (5.70 gms/0.02289 moles) and 50 ml of 2M aqueous sodium carbonate solution were charged in 75 ml toluene, followed by tetrakis (triphenyl phosphine) palladium (1.5 gms). The resultant mixture was stirred at 70- 75°C for 1 hour. The reaction mass was cooled to 25°C and extracted in ethyl acetate (30ml), The organic layer was washed with brine, dried over anhydrous sodium sulphate and the clear filtrate was distilled off completely.
The residue was stirred in 40 ml THF under inert atmosphere. To the reaction mass, 2N NaOH (11 ml) was slowly added at 25-30°C and stirred further at reflux for 5 hours. The reaction mass was cooled to 25°C and filtered through celite. The reaction mass was

acidified with diluted concentrated HCI. The reaction mass was further stirred for 30 minutes. The resulting solid was isolated by filtration, washed with water until a neutral pH and dried under vacuum to yield 3.3 gms of the titled compound. Efficiency: 72%
Preparation of 2-(3-formyl-4-hvdroxy phenyl )-4-methyl-thiazole-5-carboxylic acid (Compound VII)
To a solution of 2-(4-hydroxy phenyl)-4-methyl-thiazole-5-carboxylic acid (38 gms: 0.16 moles) in methane sulphonic acid (320 ml) was slowly added hexamine (63.15 gms, 0.44 moles) at 5-10°C. The reaction mass was heated to 80 - 85°C and maintained for 6 hours. The reaction mass was cooled to 25-30°C and diluted with ice water (1.0 lit). It was further stirred for 3 hours and the solid was isolated by filtration, washed with water, dried at 60-70°C to yield 26.7 gms of the title compound. Efficiency: 62.8 %.
Preparation of 2-(3-formyl-4-isobutyloxy phenyl)-4-methyl-thiazole-5-carboxylic acid isobutyl ester (Compound VIII)
To a stirred solution of compound VII (5.0 gms/0.019 moles), K2C03 (10.5 gms/0.076 moles) and Kl (0.5 gms) in 50 ml DMSO was slowly added iso-butyl bromide (10.4 gms/0.076 moies).The reaction mass was heated to 75-80°C for 7 hours. The reaction mass was cooled to 25-30°C, diluted with ice water (250 ml) and further stirred for 1/2 hour. The solid was isolated by filtration, washed with water, dried at 60-70°C to yield 6.55 gms of the title compound. Efficiency: 92 %.
Preparation of iso-butyl ester of fcbuxostat (Compound IX)
To a stirred solution of compound VIII (6.0 gms/0.016 moles) in 51 ml of formic acid was added hydroxylamine hydrochloride (1.43 gms/0.020 moles) in lots, followed by sodium formate (1.74 gms/0.025 moles). The reaction mass was heated to 99-100°C for 10 hours. The reaction mass was cooled to 25-30°C and diluted with ice water (500 ml), It was further stirred for 1/2 hour and the solid was isolated by filtration, washed with water, dried at 60-65°C to yield 5.55 gms of the title compound. Efficiency: 93.27%.

Preparation of febuxostat
To a stirred solution of NaOH (0.64 gms/0.016 moles) in 50.0 ml ethanol, was added iso-butyl ester of febuxostat (5.0 gms/0.013 moles). The reaction mass was heated to reflux for 4 hours. Ethanol was distilled under vacuum. To the reaction mass, THF (40 ml) and water (120 ml) were added and cooled to 10°C. The reaction mass was acidified with conc. HCI and stirred for 1 hr at 25-3G°C. The solid was isolated by filtration, washed with water, dried at 60-65°C to yield 3.81 gms of the title compound. Efficiency: 89.85%.
The solid was purified from methanol/water and recrystallized from IPA to yield 2.8 gms of febuxostat. Efficiency: 73.6%.
It will be appreciated that the invention may be modified within the scope of the appended claims.

We claim,
1. A process for preparing febuxostat of formula (I) or a pharmaceutical ly acceptable salt thereof, the process comprising: condensing a compound of formula A with a compound of formula B to form an ester of febuxostat; hydrolyzing the ester of febuxostat to febuxostat, and optionally converting the febuxostat to a pharmaceutically acceptable salt thereof,

wherein: R' is an activating group selected from boronic acid or lithium; R is selected from optionally substituted C1-4 alkyl or optionally substituted aryl; L is a leaving group selected from diazo, halo, -OS02R", -OCOR" or-0-Si(R")3; and R'' is selected from optionally substituted C1-4 alkyl or optionally substituted aryl.
2. A process according to claim 1, wherein halo is selected from chloro or bromo, preferably bromo.
3. A process according to claim 1 or 2, wherein the condensation reaction is carried out in the presence of a metallic compound catalyst, base and a solvent.
4. A process according to claim 3, wherein the metallic compound is selected from the group consisting of palladium, nickel, rhodium, ruthenium, a metallic salt and a

metallic complex, a palladium (0) ligand complex selected from bis-acetylacetonato
palladium (II), palladium tri tert-butyl phosphine, palladium trifluoroacetate, bis-
(dibenzylideneacetone) palladium (0), Pd salt/Pd(N,N-dimethyl β-alaninate)2,
tris(dibenzylidene acetone) dipalladium [Pd2(dba)3],
Tetrakis(triphenyIphosphine)palladium(0) Pd[P(C6H5)3]4, dichloro[1 ,1-
bis(diphenylphosphino)ferrocene]paNadium (II) [PdC(2(dppf)], 1,4-
bis(diphenyiphosphino)butane palladium (II) chloride [PdCb(dppb)],
dichlorobis(tricyclohexylphosphine) palladium (II) [PdCl2(PCy3]2], dichloro[l,F-bis(di-tert-butylphosphino)ferrocene]pa!ladium (II) [PdCl2(dtbp)], palladium black, palladium chloride, palladium acetate and palladium catalysts over polymeric supports; preferably tetrakis (triphenyl phosphene) palladium(O).
5. A process according to claim 3 or 4, wherein the base is selected from sodium methoxide, sodium ethoxide, sodium acetate, sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate, preferably aqueous sodium carbonate.
6. A process according to claim 3, 4 or 5, wherein the solvent is selected from the group consisting of aromatic hydrocarbons, aprotic polar solvents, protic polar solvents, aliphatic ethers, mixtures of water and one or more organic solvents.
7. A process according to claim 6, wherein the solvent is toluene.
8. A process according to any preceding claim, wherein the hydrolysis is carried out in the presence of a base or an acid in a solvent.
9. A process according to claim 8, wherein a base is used for the hydrolysis, and the base is selected from the group consisting of sodium hydroxide and potassium hydroxide.
10. A process according to claim 8, wherein an acid is used for the hydrolysis, and the acid is selected from the group consisting of hydrochloric acid and sulfuric acid.

11. A process according to claim 8, 9 or 10, wherein the solvent for the hydrolysis is selected from the group consisting of THF, water, methanol, ethanol, propanol and mixtures thereof.
12. A process according to any preceding claim, wherein the condensation and hydrolysis steps are carried out without isolation of the ester of febuxostat.
13. A process according to claim 1, wherein R' is boronic acid and compound A is prepared by: i) reacting 5-bromo-2-hydroxybenzaldehyde with an isobutyl halide selected from the group consisting of isobutyl bromide, isobutyl chloride or isobutyl iodide, preferably isobutyl bromide, in the presence of a base and a solvent to obtain a compound of formula III; ii) treating compound III with hydroxylamine or a salt thereof in the presence of a dehydrating agent and a base to obtain a compound of formula IV; Hi) reacting compound IV with an organolithium compound in a solvent to yield a compound of formula V; and reaction of compound V with a trialkyl borate and subsequent hydrolysis with an acid to obtain compound A.

14. A process according to claim 13, wherein the reaction is carried out without isolation of intermediate compound V.
15. A process according to claim 1, wherein L is bromo and compound B is prepared by: reacting thiourea with 2-chloroacetoacetic acid alkyl ester in the presence of a solvent

to obtain compound 1, wherein R is as defined in claim 1, ii) diazotizing and then brominating compound 1 using a diazotizing agent/deaminating agent and brominating agent respectively in the presence of a solvent to obtain compound B.

16. A process for preparing a compound of formula IX wherein Rl and R2 are same or different and are selected from optionally substituted alky]; which process comprises: a) formylating compound of formula VI wherein Rl is H or optionally substituted alkyl with a formylating agent in the presence of an organic solvent to form compound VII, wherein Rl is H or optionally substituted alkyl; b) alkylating compound VII using an alkylating agent in the presence of an organic solvent to obtain compound VIII, wherein Rl and R2 are same or different and are selected from optionally substituted alkyl and; c) converting compound VIII with hydroxyl amine or a salt thereof in the presence of a dehydrating agent to obtain the compound of formula IX.

17. A process for preparing a compound of formula VIII comprising the steps of: (a) alkylating compound VI, using an alkylating agent in the presence of an organic solvent to obtain compound X;


wherein Rl and R2 are same or different and are selected from optionally substituted alkyl; and (b) formylating the compound of formula X with a formylating agent in the presence of an organic solvent to form compound VIII.
18. A process according to claim 17, wherein the process further comprises converting the compound of formula IX to febuxostat.
19. A process according to claim 18, wherein R2 is an isobutyl group and R1 is optionally substituted alkyl and the conversion comprises hydrolyzing the ester of febuxostat of formula IX using a hydrolyzing agent in the presence of a solvent to obtain febuxostat.
20. A process substantially as herein described with reference to the examples.
21. Febuxostat or a salt thereof substantially as herein described with reference to the examples.